Determining mechanisms of bone remodeling response to high metabolic demands of aerobic exercise

About This Grant

Abstract Exercise is an important modulator of human health, and mechanical loading during strength and resistance- based exercise is well known to positively impact bone mass by enhancing osteoblast-mediated bone formation. However, there is a fundamental gap in understanding the response of bone to aerobic metabolic demands found in activities like running and cycling, and how those demands interact with the mechanical loads placed on the skeleton during exercise to differentially modulate bone mass. Emerging evidence shows that aerobic exercise induces acute elevations in the bone resorption marker carboxy-terminal telopeptide of type I collagen (CTX) without compensatory changes in bone formation, suggesting an immediate and unexplained pro-resorptive response. While well-documented, there is substantial lack of prior rigor regarding the cell source, extent, and purpose of elevated bone resorption during aerobic exercise. These questions are important because they may help facilitate the development of more precise recommendations for aerobic exercise to modulate bone health. Furthermore, they may provide greater understanding of factors governing bone loss in conditions of high metabolic demands or low energy availability that often result in fractures or additional disability in vulnerable populations. The central hypotheses of this proposal are that the source of CTX elevation during exercise exists on a spectrum between osteocyte perilacunar remodeling (PLR) and osteoclast resorption, the extent of which is governed by energy demands during exercise, and that CTX elevation is proportional to amino acid flux into skeletal muscle. These hypotheses will be tested in three distinct, non-overlapping specific aims. Aim 1 will determine the source of elevated CTX during aerobic exercise. We will selectively inhibit osteocyte perilacunar remodeling using MMP13ocy-/- mice and compare exercise-induced elevations in CTX to mice treated with pamidronate, which we have previously shown can inhibit osteoclast activity in the face of sustained PLR, or cathepsin K inhibitor, which selectively inhibits collagen degradation, but not demineralization of the bone ECM. Aim 2 will determine the relationship between CTX elevation and energy demands during exercise. We will run well-trained human subjects, and rats bred for high and low aerobic capacity, at treadmill speeds correlating with varying oxidative and non-oxidative energy demands. Subjects will run on commercial (human) and custom (rat) treadmill-interface systems to uncouple metabolic demands from biomechanical loading, and we will further modulate energy demands in the presence or absence of carbohydrate supplementation. Lastly, Aim 3 will evaluate the relationship between CTX elevation and amino acid distribution to skeletal muscle during aerobic exercise. We will assay circulating and muscle-targeted amino acids in rodent samples to quantify amino acid flux to the muscle in relation to both modulation of bone turnover and energy demands of the exercise itself.